.alpha.-Melanotropin is a naturally occurring tridecapeptide which is believed to interact with numerous receptors to induce various pharmacological activities. .alpha.-Melanotropin, also known as .alpha.-MSH and .alpha.-melanocyte stimulating hormone, has the following formula: Ac-Ser.sup.1 -Tyr.sup.2 -Ser.sup.3 -Met.sup.4 -Glu.sup.5 -His.sup.6 -Phe.sup.7 -Arg.sup.8 -Trp.sup.9 -Gly.sup.10 -Lys.sup.11 -Pro.sup.12 -Val.sup.13 -NH.sub.2
Before proceeding further, it is necessary to explain briefly the terminology used to describe polypeptides. Peptides are identified by amino acid sequence using established abbreviations. For example, as used herein, "Gly" stands for glycine, "Glu" stands for glutamic acid, "Tyr" stands for tyrosine, "Ser" stands for serine, "Met" stands for methionine, "Phe" stands for phenylalanine, "His" stands for histidine, "Arg" stands for arginine, "Trp" stands for tryptophan, "Lys" stands for lysine, "Pro" stands for proline, "Val" stands for valine, and "Cys" stands for cysteine. Polypeptide derivatives in which one or more of the amino acids have been replaced by another amino acid are often described by reference to the basic compound and the position and nature of the substitution. The position of substitution is usually identified by reference to the number of the amino acid in the sequence starting with the amino acid at the amino terminus of the peptide chain. For example, ##STR3## is written as ##STR4## signifying that cysteine has been substituted for the methionine normally found as the fourth amino acid from the amino terminus in .alpha.-melanotropin. The 4-10 subscript in the formula indicates that the named compound includes the amino acid sequence in the 4-10 positions of naturally occurring .alpha.-MSH. Additionally, amino acids may exist as stereoisomers in both L and D configurations. Thus, for example, as used herein "D-Lys" identifies the D optical isomer of Lysine.
The mechanism of action of peptide hormones and/or neurotransmitters is believed to be via interaction with receptors. A receptor is that entity, on a cell, which recognizes and binds a chemical substance. For purposes of explaining the action of .alpha.-MSH, receptors may be separated into two broad categories: receptors on the cells found in peripheral tissue, such as the muscles, liver, kidney and skin, and receptors which are on cells of the central nervous system (hereinafter sometimes referred to as CNS) such as the brain, spinal cord and the numerous nerve fibers.
The receptor binding properties of a particular compound dictate the physiological effect that a particular compound will produce. For example, one of the effects of .alpha.-MSH is to reversibly darken the skin by stimulating melanin synthesis. Another effect of .alpha.-MSH is to stimulate melanocyte dispersion. Both of these effects are peripheral.
Melanotropin exhibits a wide variety of physiological and pharmacological activities besides skin darkening, as related by the following literature references which are specifically incorporated herein by reference. These biological effects include (1) facilitated memory and behavior, as reported by Beckwith, B. E. and Sandman, C. A., Neurosci. Biobehav. Rev., 2, 311-338 (1978); Handelmann, G. E., O'Donohue, T. L., Forrester, D. and Cook, W., Peptides, 4, 145-148 (1983) and de Kloet, R., and de Weid, D., Neuroendocrinol., 6, 157-199 (1960); (2) active avoidance behavior, as reported by Van Nispen, J. W. and Greven, H. M., Pharmac. Ther., 16, 67-102 (1982); (3) fetal growth and development, as reported by Swaab, D. G. and Martin, J. T., Peptides of the par intermedia, Ciba Foundation Symposium 81, Evered, D. and Lawrenson, G., eds., Pitman Medicals, London, 363-368 (1981); (4) adipose tissue lipolysis, as reported by Ramachandran, J., Farmer, S. W., Liles, S. and Li, C. H., Biochem. Biophys. Acta, 428, 347-354 (1976); (5) thermoregulation, as reported by Clark, W. G. and Lipton, J. M., Pharmac. Ther., 22, 249-297 (1983); (6) enhanced attention or motivation and improved memory consolidation, as reported by Bohus, B., Pharmacol., 18, 113-122 (1979); Pigache, R. M. and Rigter, H., Frontiers of Hormone Research, van Wimersma Greidanus, T. B. and Rees, L. H., eds. Karger, Basel, Vol. 8, 193-207 (1981); and (7) adrenal activity, as reported by Vinson, G. P., Whitehouse, B. J., Bell, A., Etinenne, E., Morris, H. R., Nature, 284, 464-467 (1980).